Hypoxia therapy shows promise for treating mitochondrial brain disorders

Oxygen isn't always a good thing. Of course, people-and most organisms-cannot live without it. But oxygen can also be quite toxic and lead to profound health consequences.

In the brain, toxic levels of oxygen are tied to a rare and often fatal childhood condition known as 3-MGA, as well as Leigh syndrome (the most common pediatric mitochondrial disease), Parkinson's disease, and premature aging. Now, scientists at Gladstone Institutes are zeroing in on an approach that could help treat all of them: hypoxia therapy.

Hypoxia therapy, which involves reducing the oxygen available in the body, has been an ongoing line of inquiry for Gladstone Investigator Isha Jain, PhD. Over the past decade, she has explored how the low oxygen seen at high altitudes can have beneficial effects, including for Leigh syndrome, diabetes, and solid tumors.

A key question has been whether this therapeutic approach will extend to other rare and common forms of mitochondrial dysfunction and neurological conditions. So, Jain's lab set out to expand the scope of hypoxia therapy.

To this end, they collaborated with James Shorter, PhD, professor of biochemistry and biophysics at the University of Pennsylvania, and Daniel Southworth, PhD, professor of biochemistry and biophysics at UC San Francisco, on a study published in Nature Metabolism.

They showed that when a protein called HTRA2 malfunctions, it leads to a dangerous buildup of excess oxygen in the tissues. And, they found that breathing air with reduced oxygen levels dramatically extends lifespan and improves brain function in mice with motor neuron degeneration, a disorder caused by defective HTRA2.

"This protein is linked to many other conditions, so our findings suggest that hypoxia therapy could be transformative for treating many neurological diseases," says Jain, who is also a core investigator at Arc Institute.

When oxygen turns toxic

In the center of all cells are tiny power plants called mitochondria, which consume oxygen to produce the energy needed for the body to function. And the largest cellular machine inside mitochondria is called Complex 1.

"Every time we breathe, 90 percent of the oxygen we consume goes to our mitochondria," says Ankur Garg, PhD, postdoctoral fellow in Jain's lab and first author of the study. "But if Complex 1 malfunctions, the mitochondria can no longer burn off oxygen at normal rates."

When this happens, excess oxygen builds up in tissues until it becomes toxic, which can cause the brain damage linked to certain mitochondrial and neurological diseases. The scientists wanted to see if hypoxia therapy could be used to counteract that effect.

The team reanalyzed a previous large experiment to find genes that, when missing, caused cells to struggle in normal air but grew perfectly well in low-oxygen air. Then, they cross-referenced their findings with a directory of known genetic disorders. This led them to evaluate 75 genes that are directly linked to diseases where patients might benefit from hypoxia therapy.

One of the top hits was a protein called HTRA2. They showed that it works closely with another protein (CLPB) to keep Complex 1 intact.

"Together, these two proteins act like a clean-up crew inside mitochondria, preventing the machinery from becoming clogged with clumps of misfolded proteins," says Jain.

Jain and her team showed that when HTRA2 and CLPB are missing or defective, the clean-up crew fails to do its job properly, causing a key part of the Complex 1 machinery to fail.

Testing hypoxia therapy

To investigate if hypoxia therapy could be beneficial in a living organism, the scientists studied mice with a deficiency of HTRA2 protein.

By lowering the amount of oxygen the mice were breathing, the mice lived three times longer as compared to the regular atmospheric oxygen that's around 21 percent. The team also found that hypoxia therapy helped reduce inflammation in a part of the brain called the striatum.

"By showing these mice could be successfully treated with low oxygen, our study expands the potential of hypoxia therapy to a wide range of conditions that affect mitochondrial Complex 1, either directly or indirectly as in the case of HTRA2 deficiency," Garg says. "This will motivate a broader application of 'turning the oxygen dial' to conditions ranging from rare genetic diseases to common neurological conditions and beyond."

While the current study had mice inhale low oxygen, Jain and colleagues are currently developing a drug called HypoxyStat, which could provide the same benefits through a pill or injection.

"Right now, no treatments are uniformly available for mitochondrial diseases, and hypoxia therapy offers the hope that we could treat not just one, but many of these genetic conditions," Jain says. "We're working hard to make it a practical treatment for human patients in the clinic."